The principal investigator, Cristina Teixeira has demonstrated a consistent and strong commitment to both basic science research and clinical education. This Mentored Clinical Scientist Development Award (K08) is pivotal at this critical stage of her career to support her development and maturation into an independent, competitive scientist. Under the guidance of Dr. Adele Boskey (sponsor) and Dr. Kathleen Kinnally (cosponsor), the applicant will undergo a period of supervised didactic and research training to acquire new skills and expand her laboratory technical expertise, while collecting data to support an R01 application. As a clinician and a researcher in the field of bone and cartilage, Dr. Teixeira's long-term research goal is the development of novel therapeutic approaches to growth anomalies, and other debilitating cartilage pathology such as degenerative temporomandibular joint disease and osteoarthritis. The focus of this proposal is to determine the role of nitric oxide (NO) in growth plate cartilage. While studies of the role of NO in cartilage have been limited to osteoarthritis and performed in the context of a pathologic, inflammatory process, the applicant proposes to investigate NO regulation of chondrocyte function from a novel perspective, that of a chondrocyte maturation agent in growth plate cartilage. This tissue is responsible for bone elongation and growth of bones in the base of the skull and the mandibular condyle. Advanced molecular biology techniques will be applied to chick embryos and transgenic mice to determine the NO pathway regulating chondrocyte maturation. The hypothesis of this proposal is that NO regulates chondrocyte maturation by activating cGMP-dependent kinase II and inducing Runx2 activation. The aims are 1) to identify which chondrocyte maturation markers respond to NO generation, 2) to determine the cGMP-dependent pathway responsible for NO regulation of chondrocyte maturation and 3) to determine the role of NOS/NO and cGMPdependent kinase II in Runx2 expression and activation during chondrocyte maturation. This work has far reaching implications in the physiology and pathophysiology of skeletal tissues. Alterations in chondrocyte maturation and hypertrophy have catastrophic physiologic and quality of life outcomes, exemplified by severe chondrodystrophy and dwarfism. Understanding the regulation of chondrocyte maturation has important potential for developing interventional therapies in growth anomalies. Chondrocytes also play crucial roles in fracture repair and distraction osteogenesis. Soon, it may be possible to accelerate bone healing by manipulating chondrocyte hypertrophy, death and bone deposition. Moreover, understanding the basic signaling mechanisms in endochondral bone formation provides information vital to tissue engineering of bone replacement materials, important for correction of deformities like cleft palates or for reconstructive surgery after tumor removal. [unreadable] [unreadable] [unreadable]